Mechanism of the sympathoinhibition produced by the clonidine-like drugs rilmenidine and moxonidine.

Abstract

The mechanism of the sympathoinhibition produced by two new derivatives of clonidine, rilmenidine and moxonidine, was studied. One aim was to determine the receptor responsible for the central sympathoinhibition by these drugs. Rilmenidine and moxonidine were injected into the cisterna cerebellomedullaris. They decreased blood pressure and the plasma noradrenaline concentration. After rilmenidine and moxonidine, two selective alpha 2-adrenoceptor antagonists (devoid of affinity for I1 binding sites), yohimbine and SK&F86466, were given intracisternally. They completely counteracted the hypotensive effects of rilmenidine and moxonidine, indicating that alpha 2-adrenoceptors are involved in the central sympathoinhibition produced by these drugs. The other aim was to determine if peripheral presynaptic inhibition of noradrenaline release from postganglionic sympathetic neurons contributes to the overall reduction of sympathetic tone. Rilmenidine and moxonidine were injected i.v. in pithed rabbits with electrically stimulated sympathetic outflow. They dose-dependently lowered blood pressure and the plasma noradrenaline concentration and inhibited stimulation-evoked cardioacceleration. Moreover, the doses necessary for these peripheral effects were identical to the doses that reduce the sympathetic nerve firing rate and blood pressure in conscious rabbits. These observations indicate that peripheral presynaptic inhibition of noradrenaline release from postganglionic sympathetic neurons contributes to the overall reduction of sympathetic tone produced by rilmenidine and moxonidine in intact animals.